In most DNA-regulatory proteins, α-helical subunits serve as the molecular scaffolding for presentation of key amino acid side chains to their specific nucleic acid binding sites. (Cf. Steitz, T. A. Q. Rev. Biophys. 1990, 23, 205). Sequence-specific binding of these α-helical binding domains to double-stranded DNA occurs in the major groove as a consequence of multiple interactions arrived at (combinatorially) through evolutionary selection. Despite work toward the elucidation of Nature's “code” for molecular recognition of double-stranded DNA, it is not yet feasible to rationally design a peptide structure that will bind to any particular DNA duplex. (Desjarlais, J. R., Ber, J. M. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 7345; Desjarlais, J. R., Berg, J. M. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 2256; Rebar, E. J., Pabo, C. O. Science 1994, 263, 671; Jamieson, A. C., Kim, S.-H., Wells, J. A. Biochemistry 1994, 33, 5689; Choo, Y., Klug, A. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 11163; Segal, D. J., Dreier, B., Beerli, R. R., Banbus, C. F. III; Proc. Natl. Acad. Sci. U.S.A. 1999, Vol. 96, 2758). On the other hand, molecular recognition of single-stranded nucleic acids via Watson-Crick (W-C) base pairing is quite predictable and provides the basis for antisense approaches to genetic manipulation. (Antisense Research and Application; Crooke, S. T.; Springer-Verlag: Berlin, 1998).
The pioneering discovery that the (2-deoxy)ribose phosphate framework of nucleic acids could be replaced by a much simpler polyamide backbone has spawned considerable interest in “peptide nucleic acids” (PNAs) and related constructs. (Dueholm, K. L., Nielsen, P. E. New J. Chem. 1997, 21, 19; Eriksson, M., Nielsen, P. E., Q. Rev. Biophys. 1996, 29, 369). However, the merger of an α-helical peptidyl scaffold with well-defined nucleobase molecular recognition patterns (W—C base pairing for single-stranded RNA and Hoogsteen base pairing for double-stranded DNA) has not been explored. A particular advantage of such hybrid structures, termed as an α-helical peptide-based nucleic acid or αPNA, give the opportunity to functionalize the peptide scaffold itself to enhance transport, hybridization, and other properties.